Derivatives of amanita toxins and their conjugation to a cell binding molecule

Abstract

The present invention is related to novel cytotoxic agents, derivatives of Amanita toxins of Formula (I), wherein , -----, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, L, m, n and Q are defined herein, the preparation and the therapeutic uses in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

The invention claimed is: 
     
       1. A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof; or a polymorphic crystalline structures thereof; or an optical isomer, racemate, diastereomer or enantiomer thereof, 
         wherein 
         ----- represents a single bond that links any carbon position of the aromatic (indole) ring; 
            represents an optional single bond or an absent bond; 
         R 1  and R 2  are independently selected from the group consisting of H, OH, CH 2 OH, CH(OH)CH 2 OH, CH(CH 3 )CH 2 OH, CH(OH)CH 3 , C 1 -C 8  alkyl, —OR 12  (ether), C 2 -C 8  alkenyl, alkynyl, heteroalkyl, —OCOR 12  (ester), —OC(═O)OR 12  (carbonate), —OC(═O)NHR 12  (carbamate); C 3 -C 8  aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, and alkylcarbonyl; 
         R 3  and R 4  are independently selected from the group consisting of H, OH, —OR 12  (ether), —OCOR 12  (ester), —OCOCH 3  (acetate), —OCOOR 12  (carbonate), —OC(═O)NHR 12  (carbamate), —OP(O)(OR 12 )(OR 12 ′) (phosphate), OP(O)(NHR 12 )(NHR 12 ′) (phosphamide), O—SO 3   − , and O-glycoside; 
         R 5  is selected from the group consisting of H, OH, NH 2 , NHOH, NHNH 2 , —OR 12 , —NHR 12 , NHNHR 12 , —NR 12 R 12 ′, and N(H)(R 12 )R 13 CO(Aa) p , wherein Aa is an amino acid or a polypeptide, p represents 0-6; 
         R 6  is selected from the group consisting of H, OH, CH 2 OH, CH(OH)CH 2 OH, CH(CH 2 OH) 2 , CH(CH 3 )OH, CH 2 CH 2 OH, PrOH, BuOH, C 1 ˜C 8  alkyl, —OR 12  (ether), C 2 ˜C 8  alkenyl, alkynyl, heteroalkyl, or —OCOR 12  (ester); and C 3 ˜C 8  aryl, heterocyclic, or carbocyclic; 
         R 7 , R 8  and R 9  are independently selected from the group consisting of H, OH, CH 3 , CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH(OH)CH 2 OH, CH 2 CH(OH)CH 2 OH, CH(CH 2 OH) 2 , CH 2 C(OH)(CH 2 OH) 2 , CH 2 C(OH)(CH 3 )(CH 2 OH), CH 2 C(OH)(CH(CH 3 ) 2 )(CH 2 OH), CH 2 CH 2 OH, PrOH, BuOH, CH 2 COOH, CH 2 CH 2 COOH, CH(OH)COOH, CH 2 CONH 2 , CH 2 CH 2 CONH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC(═NH)NH 2 , C 1 ˜C 8  alkyl, CH 2 Ar, CH 2 SH, CH 2 SR 12 , CH 2 SSR 12 , CH 2 SSAr, CH 2 CH 2 SCH 3 , —OR 12  (ether), C 2 ˜C 8  alkenyl, alkynyl, heteroalkyl, or —OCOR 12  (ester); and C 3 ˜C 8  aryl, heterocyclic, or carbocyclic; 
         R 10  is selected from the group consisting of H, NH 2 , OH, SH, NO 2 , halogen, —NHOH, —N 3  (azido); —CN (cyano); C 1 ˜C 8  alkyl, C 2 ˜C 8  alkenyl, alkynyl, heteroalkyl; C 3 ˜C 8  aryl, heterocyclic, or carbocyclic; —OR 12  (ether), —OCOR 12  (ester), —OCOCH 3  (acetate), —OC(O)OR 12  (carbonate), —OC(O)CH(R 12 )NHAa (Aa is an amino acid group), —NR 12 R 12 ′ (amine), —NR 12 COR 12 ′ (amine), —NR 12 NR 12 ′NR 12 ″ (amine); —OCONR 12 R 12 ′(carbamate); —NR 12 (C═NH)NR 12 ′R 12 ″ (guanidinum); —NR 12 CO(Aa) p , (an amino acid or peptide, wherein Aa is an amino acid or a polypeptide, p represents 0-6); —N(R 12 )CONR 12 ′R 12 ″ (urea); —OCSNHR 12  (thiocarbamate); —SH (thiol); —SR 12  (sulfide); —S(O)R 12  (sulfoxide); —S(O 2 )R 12  (sulfone); —SO 3 , HSO 3 , HSO 2 , or a salt of HSO 3   − , SO 3   2−  or —HSO 2   − (sulphite), —OSO 3   − ; —N(R 12 )SOOR 12 ′ (sulfonamide); H 2 S 2 O 5  or a salt of S 2 O 5   2−  (metabisulfite); PO 3 SH 3 , PO 2 S 2 H 2 , POS 3 H 2 , PS 4 H 2  or a salt of PO 3 S 3− , PO 2 S 2   3− , POS 3   3− , PS 4   3−  (mono-, di-, tri-, and tetra-thiophosphate); (R 12 O) 2 POSR 12 ′ (thiophosphate ester); HS 2 O 3  or a salt of S 2 O 3   2−  (thiosulfate); HS 2 O 4  or a salt of S 2 O 4   2−  (dithionite); (P(═S)(OR 12 )(S)(OH) or a salt formed with a cation (phosphorodithioate); —N(R 12 )OR 12 ′ (hydroxylamine derivative); R 12 C(═O)NOH or a salt formed with a cation (hydroxamic acid); (HOCH 2 SO 2   − , or its salt (formaldehyde sulfoxylate); —N(R 12 )COR 12 ′ (amide); R 12 R 12 ′R 12 ″NPO 3 H (trialkylphosphor-amidate or phosphoramidic acid); ArAr′Ar″NPO 3 H (triarylphosphonium); OP(O)(OM 1 )(OM 2 ), OCH 2 OP(O)(OM 1 )(OM 2 ), OSO 3 M 1 ; O-glycoside (glucoside, galactoside, mannoside, glucuronoside, alloside, fructoside), NH-glycoside, S-glycoside and CH 2 -glycoside; M 1  and M 2  are independently H, Na, K, Ca, Mg, NH 4 , or NR 1 ′R 2 ′R 3 ′; R 1 ′, R 2 ′ and R 3 ′ are independently H, or alkyl; and Ar, Ar′, and Ar″ are C 3 -C 8  aryl or heteroaromatic group; 
         R 11  is H, C 1 ˜C 8  alkyl; C 2 ˜C 8  alkenyl, alkynyl, or heteroalkyl; or C 3 ˜C 8  aryl or heteroaryl; 
         R 12 , R 12 ′, and R 12 ″ are independently selected from the group consisting of H, C 1 ˜C 8  alkyl; C 2 ˜C 8  alkenyl, alkynyl, heteroalkyl; C 3 ˜C 8  aryl, heteroaryl, heterocyclic, and carbocyclic; 
         X is S, O, NH, SO, SO 2 , or CH 2 ; 
         m is 0 or 1; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; 
         L is a releasable linker having the formula of: -Ww-(Aa)r-Tt-; or -Ww-(Aa)r-Tt-Q; or Q-Ww-(Aa)r-Tt-; wherein W is a Stretcher unit; w is 0 or 1; Aa is an amino acid unit comprising independent amino acids; r is an integer ranging from 0 to 100, the Stretcher unit W comprises a self-immolative or a non-self-immolative component, peptidyl unit, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond, the self-immolative component comprises a 2-aminoimidazol-5-methanol compound, heterocyclic PAB analog, beta-glucuronide, and ortho or para-aminobenzylacetal; the non-self-immolative component is one of the following structures: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the (*) atom is a point of attachment of additional spacer or releasable linker, a cytotoxic agent, or a cell-binding agent; X 1 , Y 1 , Q 1 , R 12 , R 12 ′ are defined as above; r is 0˜100; p and q is independently 0, 1, 2, 3, 4, 5 or 6; 
         Spacer (T) is a linear, branched or cyclic alkyl, alkenyl, alkynyl or aryl having from 1 to 10 carbon atoms, or a polyethylene glycol (—CH 2 CH 2 O—) spacer; t is 0, or 1˜100, or T undergoes cyclization upon amide bond hydrolysis, of a substituted and unsubstituted 4-aminobutyric acid amide, substituted bicycle [2.2.1] and bicycle [2.2.2] ring systems or 2-aminophenylpropionic acid amide; 
         Q is a cell-binding agent or a functional group that enables the compound of Formula (I) to link with a cell-binding agent, or a functional group that enables the compound of Formula (I) to link with a linker attached on a cell-binding agent, the function group being selected from the group consisting of a thiol, an amine, a hydrazine, an alkoxylamino, a disulfide substituent, a maleimido, a haloacetyl group, a carboxy acid, an N-hydroxy succinimide ester, a ketone, an ester, an aldehyde, an alkynyl, an alkenyl, and a protected thiol or disulfide group: SAr, SSR 1  or SSAr, wherein Ar is an aromatic group or hetero aromatic group, the cell-binding agent being selected from the group consisting of antibodies and fragments each containing at least one binding site, lymphokines, hormones, growth factors, nutrient-transport molecules and vitamins. 
       
     
     
       2. The compound according to  claim 1  having the following Formula (Ia) (Ib), or (Ic): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, hydrated salt, or polymorphic crystalline structure thereof, 
         or an optical isomer, racemate, diastereomer or enantiomer thereof, 
         wherein R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , L and Q are defined the same as in  claim 1 . 
       
     
     
       3. The compound according to  claim 1  having the following Formula (Id): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, hydrated salt, or polymorphic crystalline structure thereof, 
         or an optical isomer, racemate, diastereomer or enantiomer thereof; 
         wherein R 1 , R 2 , R-4, R 5 , R 10 , L and Q are defined the same as in  claim 1 . 
       
     
     
       4. The compound according to  claim 1  having the following Formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), (Ia-12), (Ia-13), (Ia-14), (Ia-15), (Ia-16), (Ia-17), (Ia-18), (Ia-19), (Ia-20), (Ia-21), (Ia-22), (1a-23), (Ia-24), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ic-1), (Ic-2), (Ic-3), (Ic-4), (Ic-5), or (Ic-6): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, hydrated salt, or polymorphic crystalline structure thereof, 
         or an optical isomer, racemate, diastereomer or enantiomers thereof; 
         wherein R 10 , L and Q are defined the same as in  claim 1 . 
       
     
     
       5. The compound according to  claim 1  having the following Formula (Id-1), (Id-2), (Id-3), (Id-4), (Id-5), (Id-6), (Id-7), (Id-8), (Id-9), (Id-10), (Id-11), (Id-12), (Id-13), (Id-14), (Id-15), (Id-16), (Id-17), (Id-18), (Id-19), (Id-20), or (Id-21): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein L and Q are defined the same as in  claim 1 ; R 14  is H, PO 3   2− , SO 3   − , R 12 , —COR 12 , —COCH 3 , —COOR 12 , —CONR 12 R 12 ′, —C(═O)R 12 NH(Aa) t , wherein Aa is an amino acid or a polypeptide, t represents 0-100; —CSNHR 12  (thiocarbamate); —SOR 12  (sulfoxide); —SO 2 R 12  (sulfone); —SO 3   − , HSO 3 , HSO 2 , or a salt of H 5 O 3   − , SO 3   2−  or —HSO 2   −  (sulphite); P(O)(OM 1 )(OM 2 ), CH 2 OP(O)(OM 1 )(OM 2 ), SO 3 M 1 ; or glycoside (glucoside, galactoside, mannoside, glucuronoside, alloside, fructoside; M 1  and M 2  are independently H, Na, K, Ca, Mg, NH 4 , or NR 1 ′R 2 ′R 3 ′; R 1 ′, R 2 ′ and R 3 ′ are independently H, or C 1 ˜C 8  alkyl. 
       
     
     
       6. The compound according to  claim 1  having the following Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), (I-32), (I-33), (I-34), (I-35), (I-36), (I-37), (I-38), (I-39), (I-40), (I-41), (I-42), (I-43), (I-44), (I-45), (I-46), (I-47), (I-48), (I-49), (I-50), (I-51), (I-52), (I-53), (I-54), (I-55), (I-56), (I-57), (I-58), (I-69), (I-60), (I-61), (I-62), (I-63), (I-64), (I-65), (I-66), (I-67), (I-68), (I-69), (I-70), (I-71), (I-72), (I-73), (I-74), (I-75), (I-76), (I-77), (I-78), (I-79), (I-80), (I-81), (I-82), (I-83), (I-84), (I-85), (I-86), (I-87), (I-88), (I-89), (I-90), (I-91), (I-92), (I-93), (I-94), (I-95), (I-95) or (I-95): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, hydrated salt, or polymorphic crystalline structure thereof, or an optical isomer, racemate, diastereomer or enantiomer thereof, 
         wherein Aa, r, n, p, q and Q are defined the same as in the  claim 1 ; PEG is polyethylene glycol with the formula of —(OCH 2 CH 2 ) r . 
       
     
     
       7. A method for preparing the compound according to  claim 1 , comprising sequentially (i) aromatic nitration of an indole unit, (ii) reduction of a nitro group on a benzene ring of the indole unit to an amine, and (iii) condensation of the produced amine compound with a linker having a reactive or a reactable carboxylic group to form an amide linkage as illustrated below: 
       
         
           
           
               
               
           
         
       
       wherein R 10 , L and Q are defined the same as in  claim 1 , wherein Lv is leaving group selected from the group consisting of OH, halogen, NHS (N-hydroxyl succinimide), nitrophenol, pentalfluorophenol, and an intermediate generated from peptide coupling and from Mitsunobu reaction. 
     
     
       8. The compound according to  claim 1 , wherein the linker L is selected from the group consisting of: R 12 , OR 12 , OR 12 O, NHR 12 , NHR 12 NH, NR 11 R 12 , SR 12 S, OR 12 NH, OR 12 Ar, NHR 12 Ar, NR 11 R 12 NR 12 ′R 12 ″, —(CR 11 R 12 ) p (Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (CR 12 ′R 12 ″) q (Aa) r (OCH 2 CH 2 ) t —, -(Aa) r (CR 11 R 12 ) p (CR 12 ′R 12 ″) q —(OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (CR 12 ′R 12 ″) n (OCH 2 CH 2 ) t (Aa) r , —(CR 11 R 12 ) p (CH═CH)(CR 12 ′R 12 ″) q (Aa) r (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (NR 12 ′CO)(Aa) r (CR 12 ′R 12 ′—(OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (Aa) t (NHCO)(CR 12 ′R 12 ″) q —(OCH 2 CH 2 ) r , (CR 11 R 12 ) p (OCO)(Aa) r -(CR 12 ′R 12 ″) q —(OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (OCNR 7 )(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (CO)-(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (NR 11 CO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p —(OCO)(Aa) r (CR 12 ′R 12 ″) q —(OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (OCNR 7 )(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p (CO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —(CR 11 R 12 ) p -phenyl-CO(Aa) r (CR 12 ′R 12 ″) q , —(CR 11 R 12 ) p —(CR 11 R 12 ) p -furyl-CO-(Aa) t (CR 12 ′R 12 ″) q , —(CR 11 R 12 ) p -oxazolyl-CO(Aa) r (CR 12 ′R 12 ″) q , —(CR 11 R 12 ) p -thiazolyl-CO(Aa) r (CR 12 ′R 12 ″) q , —(CR 11 R 12 ) p -thienyl-CO(CR 12 ′R 12 ″) q , —(CR 11 R 12 ) p -imidazolyl-CO—(CR 12 ′R 12 ″) q —, —(CR 11 R 12 ) p -morpholino-CO(Aa) r (CR 12 ′R 12 ″) q —, —(CR11R 12 ) p -piperazino-CO(Aa) r -(CR 12 ′R 12 ″) q —, —(CR 11 R 12 ) p —N-methylpiperazin-CO(Aa) r (CR 12 ′R 12 ″) q —, —(CR 11 R 12 ) p (Aa) r -phenyl-, —(CR 11 R 12 ) p -(Aa) r -furyl-, —(CR 11 R 12 ) p -oxazolyl(Aa) r -, —(CR 11 R 12 ) p -thiazolyl-(Aa) r , —(CR 11 R 12 ) p -thienyl-(Aa) r -, —(CR 11 R 12 ) p -imidazolyl(Aa) r , —(CR 11 R 12 ) p -morpholino-(Aa) r -, —(CR 11 R 12 ) p -piperazino-(Aa) r , —(CR 11 R 12 ) p —N-methylpiperazino-(Aa) r -, —K(CR 11 R 12 ) p -(Aa) r (CR 12 ′R 12 ″) q  (OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (CR 11 ′R 12 ″) q (Aa) r (OCH 2 CH 2 ) t —, —K(Aa) r (CR 11 R 12 ) p (CR 12 ′R 12 ″) q —(OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) r (Aa) t , —K(CR 11 R 12 ) p (CR 7 ═CR 8 )(CR 12 ′R 12 ″) q -(Aa) r (OCH 2 CH 2 ) t —, —K(CR 11 R 12 ) p (NR 7 CO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (Aa) t (NR 7 —CO)(CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (OCO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(CR 11 R 12 )p(OCNR 7 )(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t —, —K(CR 11 R 12 ) p (CO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(—CR 11 R 12 ) p (NR 11 CO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (OCO)(Aa) r (CR 11 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (OCNR 7 )(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) t , —K(CR 11 R 12 ) p (CO)(Aa) r (CR 12 ′R 12 ″) q (OCH 2 CH 2 ) r Q, —K(CR 11 R 12 ) p -phenyl-CO-(Aa) r (CR 12 ′R 12 ″) q —, —K(CR 11 R 12 ) p -furyl-CO(Aa) t -(CR 12 ′R 12 ″) q , —K(CR 11 R 12 ) p -oxazolyl-CO(Aa) r (CR 12 ′R 12 ″) q —, —K(CR 11 R 12 ) p -thiazolyl-CO(Aa) t -(CR 12 ′R 12 ′) q , —K(CR 11 R 12 ) p -thienyl-CO(CR 12 ′R 12 ″) q —, —K(CR 11 R 12 ) p -thiazolyl-CO—(CR 12 ′R 12 ″) q , —K(CR 11 R 12 ) p -morpholino-CO(Aa) t (CR 12 ′R 12 ″) q —, —K(CR 11 R 12 ) p -piperazino-CO-(Aa) r (CR 12 ′R 12 ″) q —, —K(CR 11 R 12 ) p —N-methylpiperazin-CO(Aa) r -(CR 11 R 12 ″) q , —K(CR 11 R 12 ) p -(Aa) r -phenyl-, —K(C 11 R 12 ) m -(Aa) r -furyl-, —K(C 11 R 12 ) p -oxazolyl(Aa) r , —K(CR 11 R 12 ) m -thiazolyl-(Aa) r -, —K(CR 11 R 12 ) p -thienyl-(Aa) r , —K(CR 11 R 12 ) p -imidazolyl(Aa) r , —K((CR 11 R 12 ) m -morpholino-(Aa) r , —K(CR 11 R 12 ) p -piperazino-(Aa) t -, and —K(CR 11 R 12 ) m N-methylpiperazino-(Aa) r ,
 wherein K is NR 12 , O, S, Se, B, or C 3 ˜C 10  of Ar or heterocyclic; wherein Aa, r, n, p, q, t, R 7 , R 11 , R 12 , R 12 ′, R 12 ″ are as defined in  claim 1 . 
 
     
     
       9. The compound according to  claim 1  having the following formula (II-1)-(II-91): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Aa, L, m, n, p, Q, r, R 1 , and R 2 , are described the same as in  claim 1 ; CBA is a cell-binding agent. 
     
     
       10. The compound of  claim 1 , wherein the cell binding agent is a full-length antibody (polyclonal and monoclonal antibody); a single chain antibody; a diabody, a triabody, a fragments of antibody (Fab, Fab′, F(ab′) 2 , Fv, a fragment produced by a Fab expression library, an anti-idiotypic (anti-Id) antibody, CDR's, and an epitope-binding fragment of any of the above which immuno-specifically bind to cancer cell antigens, viral antigens or microbial antigens; interferon (type I, II, III); a peptide; a lymphokine IL-2, IL-3, IL-4, IL-6, GM-CSF, interferon-gamma (IFN-γ); a hormone, insulin, TRH (thyrotropin releasing hormone), MSH (melanocyte-stimulating hormone), a steroid hormone, androgens, estrogens, melanocyte-stimulating hormone (MSH); a growth factor and a colony-stimulating factor, an epidermal growth factors (EGF), a granulocyte-macrophage colony-stimulating factor (GM-CSF), a transforming growth factors (TGF), TGFα, TGFβ; a insulin and insulin like growth factor (IGF-I, IGF-II) G-CSF, M-CSF and GM-CSF; a vaccinia growth factor (VGF); a fibroblast growth factor (FGFs); a smaller molecular weight protein, poly-peptide, peptides and peptide hormones, bombesin, gastrin, gastrin-releasing peptide; a platelet-derived growth factor; an interleukin and a cytokine, interleukin-2 (IL-2), interleukin-6 (IL-6), a leukemia inhibitory factor, a granulocyte-macrophage colony-stimulating factor (GM-CSF); a vitamin, folate; an apoprotein and a lycoproteins; transferrin; a sugar-binding protein or a lipoproteins, a lectin; a cell nutrient-transport molecule (transferrin); and a small molecular inhibitor, prostate-specific membrane antigen (PSMA) inhibitor and small molecular tyrosine kinase inhibitors (TKI); peptides, or peptide analogs, proteins including conjugated proteins that are able to bind targeted cells; a non-peptides or any other cell binding molecule or substance in a form of bioactive polymer, bioactive dendrimer, nanoparticle, liposome, or viral capside. 
     
     
       11. The compound according to  claim 1 , wherein L is one or more linker components of 6-maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe” or “af”), glycine-glycine, a nature peptides containing up to 6 the same or different natural amino acids (dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide), p-aminobenzyloxycarbonyl (“PAB”), N-succinimidyl 4-(2-pyridylthio)pentanoate (“SPP”), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate (“SMCC”), N-Succinimidyl (4-iodo-acetyl)aminobenzoate (“SIAB”), ethyleneoxy (—CH 2 CH 2 O—) as one or up to 100 repeating units (“EO” or “PEO”), or one or more components that are illustrated below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 10  is defined the same as in  claim 1 ; R 15 , R 16  and R 17  are independently selected from the group consisting of —C 1 ˜C 8  alkyl or alkylene-, carbocyclo-, —O-(C 1 ˜C 8  alkyl)-, —NH—(C 1 ˜C 8  alkyl)-, -arylene-, —C 1 ˜C 8  alkylene-arylene-, -arylene, —C 1 ˜C 8 alkylene-, —C 1 ˜C 8  alkylene-(C 1 ˜C 8  carbocyclo)-, —(C 3 ˜C 7  carbocyclo)-C 1 ˜C 8  alkylene-, —C 3 ˜C 8  heterocyclo-, alkylene-(C 3 ˜C 8  heterocyclo)-, —(C 3 ˜C 8  heterocyclo)-C 1 ˜C 9  alkylene-, —(CH 2 CH 2 O) k —, —(CH(CH 3 )CH 2 O) k —, and —(CH 2 CH 2 O) k —CH 2 —; k is an integer ranging from 1-50; X′″, Y″ and Z′″ are independently NH, O or S. 
       
     
     
       12. The compound according to  claim 1 , having any one of the specific conjugation structures of (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9), (III-10), (III-11), and (III-12) described in  FIGS. 31A-31F   
       wherein “═” represents either a single bond or a double bond; L 1  and L 2  are, the same or different, independently defined the same as L in  claim 1 ; X 1  and X 2 , are, the same or different, independently NH, N(R 1 ), O, S, CH 2 , or Ar, wherein R 1  is C 1 -C 6  alkyl and Ar is an aromatic or heteroaromatic ring; wherein Drug 1  and Drug 2  are the same or different, independently a moiety linked to L other than Q in Formula (I) of  claim 1 , or one of Drug 1  and Drug 2  is the moiety linked to L other than Q in Formula (I) of  claim 1 , the other of Drug 1  and Drug 2  is absent, (OCH 2 CH 2 ) r OR 10 , (OCH 2 CH(CH 3 )) p OR 10 , NH(CH 2 CH 2 O) p R 10 , NH(CH 2 CH(CH 3 )O) p R 10 , N[(CH 2 CH 2 O) p R 10 ][(CH 2 CH 2 O) r R 5 ], (OCH 2 CH 2 ) p COOR 10 , or CH 2 CH 2 (OCH 2 CH 2 ) p COOR 10 , wherein p, r, R 10  are described the same as in  claim 1 , when both Drug 2  and L 2  are absent, X 2  is NH 2  or OH. 
     
     
       13. The compound according to  claim 1 , comprising an IgG antibody linked to one of the following linkage structures of (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), and (IV-6): 
       
         
           
           
               
               
           
         
       
       wherein “═” represents either a single bond or a double bond; Drug is a moiety linked to L other than Q in Formula (I) of  claim 1 ; 
       
         
           
           
               
               
           
         
       
       represents a site on an antibody; L, X, n and R 12  are defined the same as in  claim 1 . 
     
     
       14. A process for forming the compound according to  claim 12  comprising a step of reducing a dithiol bond in an antibody with one or more reducing agent selected from the group consisting of dithiothreitol (DTT), dithioerythritol (DTE), L-glutathione (GSH), tris (2-carboxyethyl) phosphine (TCEP), 2-mercaptoethylamine (13-MEA), and beta mercaptoethanol 2-ME), the reducing agent being optionally loaded or covalently bonded to a solid polymer or a solid particle, wherein the polymer or the particle is selected from the group consisting of polyethene, polyacrylate, silica, crossed-linked silica (2-mercaptoethyl)silica, (aminoethyl)silica, (aminopropyl)silica), polyethylene terephthalate, polyethylene glycol, polystyrene, poly(isopropyl acrylate), dextrans (Sephadex, cross-linked dextran), isopropylacrylamide butyl methacrylate copolymer, and polysaccharide polymer (agarose, agar, agaropectin, Sepharose). 
     
     
       15. The compound according to  claim 12 , when one of Drug 1  and Drug 2  is a moiety linked to L other than Q in Formula (I), the other one of Drug 1  and Drug 2  is selected from the group consisting of a protein, an antibody (a monoclonal or polyclonal antibody, antibody dimers, antibody multimers, a bispecific or trispecific antibody, a single chain antibody, an antibody fragment that binds to the target cell), a chromophore molecule, a tubulysin derivative, a maytansinoid, a taxanoid (taxane), a CC-1065 analog, a daunorubicin or doxorubicin compound, a benzodiazepine dimer (dimers of pyrrolobenzodiazepine (PBD), tomaymycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, or oxazolidinobenzodiazepines), a calicheamicin, a dolastatin or auristatin derivative (monomethyl auristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, Auristatins 2-AQ, 6-AQ, EB (AEB), EFP (AEFP)), a duocarmycin, a siRNA, and an enzyme. 
     
     
       16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1 , and a pharmaceutically acceptable excipient selected from the group consisting of one or more components of 0.002%˜1% of polysorbate (polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80), sodium lauryl sulfate, triton X-100; 0.01% 10% of a binder (disaccharides: sucrose, lactose, trehalose or maltose; or sugar alcohols: xylitol, sorbitol or maltitol, or polyethylene glycol), and 0.01%˜10% of a pharmaceutical buffering agent (citrate, succinate acetate, phosphate, or borate) at a pH of 4.5-9.5. 
     
     
       17. A method for inhibiting abnormal cell growth or treating a proliferative disorder including cancers, benign or malignant tumors; leukemia and lymphoid malignancies; neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, angiogenic and immunologic disorders; inflammatory; autoimmune disorders; destructive disorders; bone disorder; infectious disease; viral disease; fibrotic disease; neurodegenerative disorder; pancreatitis or kidney disease; in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to  claim 1 . 
     
     
       18. The pharmaceutical composition according to  claim 16  further comprising one or more synergistic drugs of a chemotherapeutic agent, radiation therapy, immunotherapy agent, autoimmune disorder agent, or anti-infectious agent. 
     
     
       19. The compound according to  claim 1 , wherein the cell binding agent is an antibody, an antibody fragment, a diabody, a tri(a)body, an epidermal growth factor (EGF), a prostate specific membrane antigen (PSMA) inhibitor, a melanocyte stimulating hormone (MSH), a thyroid stimulating hormone (TSH), a polyclonal antibody, a somatostatin, a folate, a matriptase inhibitor, an estrogen, an estrogen analogue, a designed ankyrin repeat proteins (DARPins), an androgen, or an androgen analogue. 
     
     
       20. The compound according to  claim 1 , wherein Q targets cells selected from the group consisting of tumor cells; virus infected cells; microorganism infected cells; parasite infected cells; autoimmune cells; activated cells; myeloid cells; activated T-cells, B cells, or melanocytes; cells expressing antigen of CD3, CD4, CD5, CD6, CD7, CD8, CD9, CD10, CD11a, CD11b, CD11c, CD12w, CD14, CD15, CD16, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD51, CD52, CD53, CD54, CD55, CD56, CD58, CD59, CD61, CD62E, CD62L, CD62P, CD63, CD66, CD68, CD69, CD70, CD72, CD74, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD86, CD87, CD88, CD89, CD90, CD91, CD95, CD96, CD98, CD100, CD103, CD105, CD106, CD109, CD117, CD120, CD125, CD126, CD127, CD133, CD134, CD135, CD137, CD138, CD141, CD142, CD143, CD144, CD147, CD151, CD147, CD152, CD154, CD156, CD158, CD163, CD166, CD168, CD174, CD180, CD184, CDw186, CD194, CD195, CD200, CD200a, CD200b, CD209, CD221, CD227, CD235a, CD240, CD262, CD271, CD274, CD276 (B7-H3), CD303, CD304, CD309, CD326, 4-1BB, SAC, 5T4 (Trophoblast glycoprotein, TPBG, 5T4, Wnt-Activated Inhibitory Factor 1 or WAIF1), Adenocarcinoma antigen, AGS-5, AGS-22M6, Activin receptor-like kinase 1, AFP, AKAP-4, ALK, Alpha intergrin, Alpha v beta6, Amino-peptidase N, Amyloid beta, Androgen receptor, Angiopoietin 2, Angiopoietin 3, Annexin A1, Anthrax toxin protective antigen, Anti-transferrin receptor, AOC3 (VAP-1), B7-H3,  Bacillus anthracis  anthrax, BAFF (B-cell activating factor), BCMA, B-lymphoma cell, bcr-abl, Bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate antigen 125, MUC16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg,  Canis lupus familiaris  IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11(C-C motif chemokine 11), CCR4 (C-C chemokine receptor type 4, CD194), CCR5, CD3E (epsilon), CEA (Carcinoembryonic antigen), CEACAM3, CEACAM5 (carcino-embryonic antigen), CFD (Factor D), Ch4D5, Cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), Clumping factor A, cMet, CRIPTO, FCSFIR (Colony stimulating factor 1 receptor, CD115), CSF2 (colony stimulating factor 2, Granulocyte-macrophage colony-stimulating factor (GM-CSF)), CSP4, CTLA4 (cytotoxic T-lymphocyte-associated protein 4), CTAA16.88 tumor antigen, CXCR4 (CD184), C—X—C chemokine receptor type 4, cyclic ADP ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL4 (delta-like-ligand 4), DPP4 (Dipeptidyl-peptidase 4), DR5 (Death receptor 5),  E. coli  shiga toxin type-1,  E. coli  shiga toxin type-2, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, Endoglin (CD105), Endothelin B receptor, Endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, Episialin, ERBB2 (Epidermal Growth Factor Receptor 2), ERBB3, ERG (TMPRSS2 ETS fusion gene),  Escherichia coli , ETV6-AML, FAP (Fibroblast activation protein alpha), FCGR1, alpha-Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR (folate receptor), Folate receptor alpha, Folate hydrolase, Fos-related antigen 1F protein of respiratory syncytial virus, Frizzled receptor, Fucosyl GM1, GD2 ganglioside, G-28 (a cell surface antigen glyvolipid), GD3 idiotype, GloboH, Glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor a-chain, Growth differentiation factor 8, GP100, GPNMB (Trans-membrane glycoprotein NMB), GUCY2C (Guanylate cyclase 2C, guanylyl cyclase C(GC-C), intestinal Guanylate cyclase, Guanylate cyclase-C receptor, Heat-stable enterotoxin receptor (hSTAR)), Heat shock proteins, Hemagglutinin, Hepatitis B surface antigen, Hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2/neu, HER3 (ERBB-3), IgG4, HGF/SF (Hepatocyte growth factor/scatter factor), HHGFR, HIV-1, Histone complex, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, Human chorionic gonadotropin, HNGF, Human scatter factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1 (Intercellular Adhesion Molecule 1), Idiotype, IGFIR (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN-γ, Influenza hemagglutinin, IgE, IgE Fc region, IGHE, IL-1, IL-2 receptor (interleukin 2 receptor), IL-4, IL-5, IL-6, IL-6R (interleukin 6 receptor), IL-9, IL-10, IL-12, IL-13, IL-17, IL-17A, IL-20, IL-22, IL-23, IL31RA, ILGF2 (Insulin-like growth factor 2), Integrins (α4, α IIb β 3 , αvβ 3 , α 4 β 7 , α 5 β 1 , α 6 β 4 , α 7 β 7 , α 11 β 3 , α 5 β 5 , αvβ 5 ), Interferon gamma-induced protein, ITGA2, ITGB2, KIR2D, Kappa Ig, LCK, Le, Legumain, Lewis-Y antigen, LFA-1 (Lymphocyte function-associated antigen 1, CD11a), LHRH, LINGO-1, Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MARTI, MCP-1, MW (Macrophage migration inhibitory factor, or glycosylation-inhibiting factor (GIF)), MS4A1 (membrane-spanning 4-domains subfamily A member 1), MSLN (mesothelin), MUC1 (Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (monocyte chemotactic protein 1), MelanA/MART1, ML-IAP, MPG, MS4A1 (membrane-spanning 4-domains subfamily A), MYCN, Myelin-associated glycoprotein, Myostatin, NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME), NGF, Neural apoptosis-regulated proteinase 1, NOGO-A, Notch receptor, Nucleolin, Neu oncogene product, NY-BR-1, NY-ESO-1, OX-40, OxLDL (Oxidized low-density lipoprotein), OY-TES1, P21, p53 nonmutant, P97, Page4, PAP, Paratope of anti-(N-glycolylneuraminic acid), PAX3, PAX5, PCSK9, PDCD1 (PD-1, Programmed cell death protein 1, CD279), PDGF-Rα (Alpha-type platelet-derived growth factor receptor), PDGFR-β, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, Platelet-derived growth factor receptor beta, Phosphate-sodium co-transporter, PMEL 17, Polysialic acid, Proteinase3 (PRI), Prostatic carcinoma, PS (Phosphatidylserine), Prostatic carcinoma cells,  Pseudomonas aeruginosa , PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI), CD240), Rhesus factor, RANKL, RhoC, Ras mutant, RGS5, ROBO4, Respiratory syncytial virus, RON, ROR1, Sarcoma translocation breakpoints, SART3, Sclerostin, SLAMF7 (SLAM family member 7), Selectin P, SDCI (Syndecan 1), sLe(a), Somatomedin C, SIP (Sphingosine-1-phosphate), Somatostatin, Sperm protein 17, SSX2, STEAP1 (six-transmembrane epithelial antigen of the prostate 1), STEAP2, STn, TAG-72 (tumor associated glycoprotein 72), Survivin, T-cell receptor, T cell transmembrane protein, TEM1 (Tumor endothelial marker 1), TENB2, Tenascin C (TN-C), TGF-α, TGF-β (Transforming growth factor beta), TGF-β1, TGF-β2 (Transforming growth factor-beta 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF-α, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF-13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (Tumor necrosis apoprosis Inducing ligand Receptor 1), TRAILR2 (Death receptor 5 (DR5)), tumor-associated calcium signal transducer 2, tumor specific glycosylation of MUC1, TWEAK receptor, TYRP1 (glycoprotein 75), TRP-2, Tyrosinase, VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2, vimentin, WT1, XAGE 1, cells expressing any insulin growth factor receptors, and epidermal growth factor receptors. 
     
     
       21. A method for treatment of a cancer, autoimmune disorder, infectious disease or viral disease in vitro, in vivo, or ex vivo, comprising utilizing the pharmaceutical composition according to  claim 16 . 
     
     
       22. The compound according to  claim 1 , wherein the self-immolative linker component has one of the following structures: 
       
         
           
           
               
               
           
         
       
       wherein the (*) atom is a point of attachment of additional spacer or releasable linker unit, or a cytotoxic agent, or the cell binding agent (CBA); X 1 , Y 1 , Z 2  and Z 3  are independently NH, O, or S; Z 1  is independently H, NH, O or S, v is 0 or 1; Q 1  is independently H, OH, C 1 ˜C 6  alkyl, (OCH 2 CH 2 ) n F, Cl, Br, I, OR 12 , SR 12 , NR 12 R 12 ′, N═NR 12 , N═R 12 , NR 12 R 12 ′, NO 2 , SOR 12 R 12 ′, SO 2 R 12 , SO 3 R 12 , OSO 3 R 12 , PR 12 R 12 ′, POR 12 R 12 ′, PO 2 R 12 R 12 ′, OPO(OR 12 )(OR 12 ′), or OCH 2 PO(OR 12 (OR 12 ′), wherein R 12  and R 12 ′ are as defined the same as in  claim 1 . 
     
     
       23. The compound according to  claim 22 , wherein R 12  and R 12 ′ are independently H, C 1 ˜C 8  alkyl; C 2 ˜C 8  alkenyl, alkynyl, heteroalkyl; C 3 ˜C 8  aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl; or a pharmaceutical cation salt thereof. 
     
     
       24. The compound according to  claim 1 , wherein Q is one of the following formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein D is H, —NO 2 , SO 3   − , CN, or F; Aa, r, p, q, m, and n are described the same as in  claim 1 ; w and w′ are 0 or 1 independently; R 1 ′, R 2 ′, R 3 ′, and R 4 ′ are independently H, CH 3 , C 2 H 5 , C 3 H 7 , CH 2 OH, or CH 2 CH 2 OH. 
     
     
       25. The compound according to  claim 6 , wherein Q is H, C 1 ˜C 8  of alkyl, alkenyl, alkynyl, aryl, cyclic, cyclohetero, haloalkyl, alkoxy, haloalkoxy alkylamino; halogen; —NO 2 ; —CN; —SH; —SSCH 3 ; —SSAc; —SSAr; —SS-Pyridine; —SS-Ar(-NO 2 ); —S-cell binding agent; or a function group of NHS ester, pentafluorophenyl ester; alkyloxyamine; aldehyde; ketone; carboxyl acid; hydrazine; amine; or thiolactone; or is linked the cell binding agent via Stretcher units (Ww) or via Spacer units (Tt), wherein W, w, T, and t are defined the same as in  claim 6 . 
     
     
       26. The compound according to  claim 12 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4 antibody. 
     
     
       27. The compound according to  claim 15 , wherein the other one of Drug 1  and Drug 2  is one of structures illustrated below:
 V-1, an antibody, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       -V-37, a siRNA, -V-38, an enzyme or protein linked from N-terminal, -V-39, an enzyme or protein linked from C-terminal, wherein R 10  are described the same as in  claim 15 , and 
       
         
           
           
               
               
           
         
       
       is a site of link to either linker L 1  or linker L 2 .